Statistical method for testing the neutral mutation hypothesis by DNA polymorphism.

So far in this course we have dealt entirely with the evolution of characters that are controlled by simple Mendelian inheritance at a single locus. There are notes on the course website about gametic disequilibrium and how allele frequencies change at two loci simultaneously, but we didn’t discuss them. In every example we’ve considered we’ve imagined that we could understand something about evolution by examining the evolution of a single gene. That’s the domain of classical population genetics. For the next few weeks we’re going to be exploring a field that’s actually older than classical population genetics, although the approach we’ll be taking to it involves the use of population genetic machinery. If you know a little about the history of evolutionary biology, you may know that after the rediscovery of Mendel’s work in 1900 there was a heated debate between the “biometricians” (e.g., Galton and Pearson) and the “Mendelians” (e.g., de Vries, Correns, Bateson, and Morgan). Biometricians asserted that the really important variation in evolution didn’t follow Mendelian rules. Height, weight, skin color, and similar traits seemed to

Human biochemical genetics

Recent advances in molecular genetic techniques will make dense marker maps available and genotyping many individuals for these markers feasible. Here we attempted to estimate the effects of ∼50,000 marker haplotypes simultaneously from a limited number of phenotypic records. A genome of 1000 cM was simulated with a marker spacing of 1 cM. The markers surrounding every 1-cM region were combined into marker haplotypes. Due to finite population size (Ne = 100), the marker haplotypes were in linkage disequilibrium with the QTL located between the markers. Using least squares, all haplotype effects could not be estimated simultaneously. When only the biggest effects were included, they were overestimated and the accuracy of predicting genetic values of the offspring of the recorded animals was only 0.32. Best linear unbiased prediction of haplotype effects assumed equal variances associated to each 1-cM chromosomal segment, which yielded an accuracy of 0.73, although this assumption was far from true. Bayesian methods that assumed a prior distribution of the variance associated with each chromosome segment increased this accuracy to 0.85, even when the prior was not correct. It was concluded that selection on genetic values predicted from markers could substantially increase the rate of genetic gain in animals and plants, especially if combined with reproductive techniques to shorten the generation interval.

https://www.genetics.org/content/genetics/157/4/1819.full.pdf

Prediction of Total Genetic Value Using Genome-Wide Dense Marker Maps

The detection of genes that control quantitative characters is a problem of great interest to the genetic mapping community. Methods for locating these quantitative trait loci (QTL) relative to maps of genetic markers are now widely used. This paper addresses an issue common to all QTL mapping methods, that of determining an appropriate threshold value for declaring significant QTL effects. An empirical method is described, based on the concept of a permutation test, for estimating threshold values that are tailored to the experimental data at hand. The method is demonstrated using two real data sets derived from F(2) and recombinant inbred plant populations. An example using simulated data from a backcross design illustrates the effect of marker density on threshold values.

/pdf/empirical-threshold-values-for-quantitative-trait-mapping-336xyasfa9.pdf

Empirical threshold values for quantitative trait mapping.

The UK Biobank project is a prospective cohort study with deep genetic and phenotypic data collected on approximately 500,000 individuals from across the United Kingdom, aged between 40 and 69 at recruitment. The open resource is unique in its size and scope. A rich variety of phenotypic and health-related information is available on each participant, including biological measurements, lifestyle indicators, biomarkers in blood and urine, and imaging of the body and brain. Follow-up information is provided by linking health and medical records. Genome-wide genotype data have been collected on all participants, providing many opportunities for the discovery of new genetic associations and the genetic bases of complex traits. Here we describe the centralized analysis of the genetic data, including genotype quality, properties of population structure and relatedness of the genetic data, and efficient phasing and genotype imputation that increases the number of testable variants to around 96 million. Classical allelic variation at 11 human leukocyte antigen genes was imputed, resulting in the recovery of signals with known associations between human leukocyte antigen alleles and many diseases.

/pdf/the-uk-biobank-resource-with-deep-phenotyping-and-genomic-2fs3jmksld.pdf

The UK Biobank resource with deep phenotyping and genomic data

A breeding programme has been undertaken by Ifremer to produce selected Ostrea edulis families which are resistant to Bonamia ostreae, a parasite which is the most significant constraint on aquaculture of this oyster. Using such families, we aimed to identify Quantitative Trait Loci (QTLs) of resistance/susceptibility to bonamiosis. We used an F2 family derived from a bi-parental cross between a wild oyster and an individual from one of the selected oyster families. A total of 550 F2 individuals from the family cohabited with wild oysters that were injected with the parasite. Mortality was checked daily over six months and heart smears were used on moribund or dying oysters to detect the presence and level of infection of the parasite. Ninety two F2 progeny were scored for 20 microsatellites and 34 AFLP primer pairs: 46 were heavily infected oysters that died during the challenge experiment and 46 were oysters that survived and in which no parasite could be detected. Sex-specific genetic linkage maps were built for the family, spanning 10 linkage groups (n=10) with an observed genome coverage of 69-84%. Fifteen AFLPs (out of 304) showed a significant difference of allele frequencies between the two phenotypically extreme groups. A QTL interval mapping approach identified 3 QTLs in the first parental map and 2 in the second. Some of the 15 markers identified in the survival analysis were mapped to the same locations as the QTLs, strengthening our results.

QTL mapping for resistance to Bonamiosis in the European Flat Oyster Ostrea edulis

The nature of an organism is defined by its complement of genes. Molecular techniques have made it possible to unravel this inherited blueprint. The Human Genome Project has as its ultimate objecti...

Mapping the complex genomes of animals and man

for genetical genomics studies Review of microarray experimental design strategies

Human population isolates provide a snapshot of the impact of historical demographic processes on population genetics. Such data facilitate studies of the functional impact of rare sequence variants on biomedical phenotypes, as strong genetic drift can result in higher frequencies of variants that are otherwise rare. We present the first whole genome sequencing (WGS) study of the VIKING cohort, a representative collection of samples from the isolated Shetland population in northern Scotland, and explore how its genetic characteristics compare to a mainland Scottish population. Our analyses reveal the strong contributions played by the founder effect and genetic drift in shaping genomic variation in the VIKING cohort. About one tenth of all high-quality variants discovered are unique to the VIKING cohort or are seen at frequencies at least ten fold higher than in more cosmopolitan control populations. Multiple lines of evidence also suggest relaxation of purifying selection during the evolutionary history of the Shetland isolate. We demonstrate enrichment of ultra-rare VIKING variants in exonic regions and for the first time we also show that ultra-rare variants are enriched within regulatory regions, particularly promoters, suggesting that gene expression patterns may diverge relatively rapidly in human isolates. Author Summary Population isolates provide a valuable window on the roles of rare genetic variation in human phenotypes, as a result of their unusual evolutionary histories, that often lead to relatively high frequencies of variants that are exceptionally rare elsewhere. Such populations show increased levels of background relatedness among individuals and are often subject to stronger genetic drift, leading to a higher frequency of deleterious variants. Here, for the first time, we present whole genome sequencing data from the Shetland population in Northern Scotland, encompassing 500 individuals, and compare these genomes to the mainland Scottish population. As expected we find the imprint of Shetland population history in the Shetland genome, with strong evidence for founder effects and genetic drift, but we also discover a relaxation of selective constraint across the genome. These influences have combined to endow the Shetland genome with thousands of ultra-rare genetic variants, not observed previously in other populations. Surprisingly these variants are significantly enriched in functional regions including protein coding regions of genes and regulatory elements. Among regulatory regions, promoters are particularly enriched for ultra-rare variants, suggesting the potential for rapid divergence of gene expression in isolates.

/pdf/increased-ultra-rare-variant-load-in-an-isolated-scottish-51fz92yi02.pdf

Chris Haley

Papers

QTL mapping for resistance to Bonamiosis in the European Flat Oyster Ostrea edulis

Mapping the complex genomes of animals and man

for genetical genomics studies Review of microarray experimental design strategies

Increased ultra-rare variant load in an isolated Scottish population impacts exonic and regulatory regions

Debrisoquine hydroxylation phenotyping: do we expect too much?